With a concentration of 35-50 g/l, human albumin is the main component in plasma. Its therapeutic use has been known for a long time, an administration of albumin being indicated, e.g., in case of an acute loss of blood or plasma or in case of failure of the vasomotoric regulation. Since the osmotic pressure of a 20% (25%) albumin solution is approximately 4 times (5 times) that of normal human serum, the effect of albumin is mainly based on its ability to maintain the osmotic pressure.
Human albumin preparations are prepared from human plasma by multiple fractionation, e.g. by a fractionation according to Cohn, or they are prepared by means of recombinant methods. On account of various materials used during its preparation or when the albumin solution is stored in glass containers, aluminum gets into the albumin preparation so that the final content of aluminum in the respective preparations may be quite substantial.
Aluminum, which constitutes one of the most frequently occurring elements in nature, has recently been increasingly associated with various diseases of the human body, primarily with diseases of the nervous and bone systems. Although the lungs and the gastro-intestinal tract form an efficient barrier for the uptake of aluminum, this barrier is no longer effective in patients receiving intravenous preparations, and the aluminum possibly present in the administered preparations may be taken up without hindrance. Thus, e.g., D. S. Milliner et al. (N. Engl. J. Med. (1985), 312, pp. 165-167) report that some albumin products comprising large amounts of aluminum have lead to diseases of the bones or to encephalitis. Aluminum is also increasingly associated with Alzheimer's disease.
Therefore, efforts have been made to keep the aluminum content of, e.g., albumin preparations low. From U.S. Pat. No. 5,372,997, e.g., a method of reducing the aluminum content of albumin preparations by using special glass containers on the one hand, and by treatment with an anion exchanger, on the other hand, has been known. The aluminum is prevented from dissolving out of glass containers by using a special glass poor in aluminum and by dealkalizing the inner surfaces thereof with an ammonium sulfate solution or with sulphurous acid. Furthermore, a treatment with a cation exchanger is carried out. Finally, for heat-treating the albumin solution, the stabilizers commonly used therefor, such as sodium N-acetyl tryptophane or sodium caprylate, are admixed.
From EP-0 484 464-B1 a method of purifying an albumin from multivalent metal ions bound thereto by substituting them by monovalent metal ions, e.g. ammonium or alkaline metal ions, has been known.
Also from U.S. Pat. No. 5,250,663 a method has been known according to which an albumin substantially free from aluminum can be obtained. This method starts with an albumin-containing fraction, a Cohn fraction, e.g., and at first various precipitations are carried out. I. a., a heat shock treatment is carried out in the presence of sodium caprylate as stabilizer and 10 to 20% ethanol. Finally, this solution is subjected to an ultrafiltration and a diafiltration. After the diafiltration, aluminum and other impurities have been removed, weak salt solutions, such as 3% NaCl, sodium acetate or, in some instances, sodium caprylate solutions being used for this diafiltration. With this use of caprylate, no exchange of salts will occur, since caprylate has already been admixed as a stabilizer for the heat shock treatment prior to diafiltration; thus, substantial amounts of citrate ions will still be present in the preparation.
As has, e.g., been described by J. C. May et al. (1992) (Vox Sang., 62, pp. 65-69), the presence of citrate ions, which have a high affinity to aluminum, plays an essential role in the uptake of aluminum (for this, cf. e.g. also R. B. Martin (1986), J. Inorgan. Biochem., 28, pp. 181-187), and thus the mere presence of citrate ions constitutes a general risk of metal ion contaminations for all the preparations.
In EP-0 696 595-A1, the citrate ions are removed in the course of a DEAE Sephadex chromatography in a method in which caprylate is used for the fractionation of albumin. Yet there is no simple exchange of citrate ions for other ions, but—on account of the high costs of the DEAE Sephadex anion exchangers—an expensive separation of citrate takes place.